Type 2 diabetes mellitus (T2D) is a disease in which a person has high blood sugar as a result of resistance of the body's tissues to the glucose-lowering effects of insulin and failure of the beta cells of the islets of Langerhans to produce enough insulin. The American Diabetes Association reports that there are 18.8 million Americans with diagnosed T2D, 7.0 million individuals with undiagnosed T2D, and another 79 million potential candidates with pre-diabetes. An annual expenditure of $174 billion is attributed to the disease; this figure from 2007 is expected to rise. Complications of T2D are the third leading cause of death in the United States; in 2007 T2D was listed as a contributing factor to over 200,000 deaths. Prolonged untreated diabetes leads to heart diseases, stroke, kidney disease, blindness, and loss of limbs from advanced peripheral vascular disease. Combined, these facts underscore the critical need for increased understanding of and treatments for T2D.
The standard of care for T2D management in children and adults is healthy eating, portion control, increased physical activity, and glucose-lowering medications. However, few of the available medications have been approved for use in children or adolescents; thus, physicians are hesitant to prescribe these medications, and in doing so, fail to prevent further beta cell destruction if hyperglycemia persists.
Obesity is a risk factor for T2D because it is usually associated with insulin resistance. However, although most people with T2D are obese, most obese people do not develop T2D because they compensate for insulin resistance by secreting more insulin. When obese people progress to develop T2D, it is because their beta cells are unable to satisfy the increased demand for insulin. Thus, most of the newer T2D treatments in the clinic or under development target beta cell dysfunction and not insulin sensitivity.
Drugs that target G protein complexes are used as T2D therapeutics. GTP-binding proteins (G proteins) are membrane-associated signaling molecules whose activity is regulated by the cycle of GTP binding (active state) and GTP hydrolysis to GDP (inactive state), followed by GDP dissociation and re-binding of GTP. Heterotrimeric G proteins are composed of a beta-gamma-dimer and a catalytically-active alpha-subunit that are tightly associated with a transmembrane G protein-coupled receptor (GPCR) in their inactive state. Upon activation by receptor-ligand interaction these G protein-GPCR complexes dissociate in order to transmit signals to downstream effectors (i.e., signal transduction).
Of the four subfamilies of heterotrimeric G protein alpha-subunits (G alpha-s, G alpha-i, G alpha-q, and G alpha-12), only those in the G alpha-s subfamily can positively regulate the catalytic activity of adenylate cyclase, increasing the conversion of ATP to cAMP. cAMP is a known potentiator of beta cell function, having been shown to augment glucose-stimulated insulin secretion (GSIS) by numerous mechanisms (Lang, Eur. J. Biochem. 259:3-17 (1999); Furman and Pyne, Curr. Opin. Investig. Drugs 7:898-905 (2006); Shibasaki et al., Proc. Natl. Acad. Sci. USA 104:19333-19338 (2007)). Furthermore, cAMP has also been shown to have proliferative and anti-apoptotic effects on beta cells (Li et al., J. Biol. Chem. 278:471-478 (2003)).
Drugs that target a specific GPCR are widely used as T2D therapeutics. The hormone glucagon-like peptide 1 (GLP-1) is secreted by specialized cells in the intestine in response to the presence of nutrients from food. Sugars, proteins and fats can all cause GLP-1 release from the gut cells. GLP-1 activates a G alpha-s-coupled receptor on beta cells to stimulate cAMP production and potentiate GSIS from beta cells of the islets of Langerhans. Although GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase (DPP)-4, stable GLP-1 analogs exenatide (Byetta®, Lilly) and liraglutide (Victoza®, Novo-Nordisk) have been shown to be clinically effective for the treatment of T2D (Furman and Pyne (2006); Triplitt, Am. J. Manag. Care 13:S47-54 (2007)). In addition, inhibitors of DPP-4, including sitagliptin (Januvia®, Merck), saxagliptin (Onglyza®, Bristol-Myers Squibb), vildagliptin (Galvus®, Novartis), and linagliptin (Tradjenta®, Eli Lilly) also lead to improved beta cell function and glucose clearance in T2D patients (Furman and Pyne, supra; Triplitt, supra).
Of all the current diabetes therapeutics, agents that stimulate beta cell cAMP production, including DPP-4 inhibitors and GLP-1 analogs, are the only ones that positively impact beta cell replication, neogenesis, and/or survival in rodent models (Xu et al., Diabetes 48:2260-2276 (1999); Wang and Brubaker Diabetologia 45:1263-1273 (2002); Sturis et al., Br. J. Pharmacol. 140-123-132 (2003); Perfetti et al., Endocrinology 141:4600-4605 (2000); Gedulin et al., Endocrinology 146:2069-2076 (2005); Farilla et al., Endocrinology 143:2069-2076 (2002)) or human islets (Farilla et al., Endocrinology 144:5149-5158 (2003)). Interestingly, GLP-1 treatment can protect both rodent and human beta cells from immune-mediated apoptosis (Sano et al., Biochem. Biophys. Res. Commun. 404:756-761 (2011); Pugazhenthi et al., Diabetologia 53:2357-2368 (2010)).
Unfortunately, not all diabetic patients respond to GLP-1-based treatments. Approximately 35-60% of diabetic patients treated with sitagliptin fail to achieve a glycosylated hemoglobin (i.e., HbAlc) target of <7% (Raz et al., Diabetologia 49:2564-2571 (2006); Aschner et al., Diabetes Care 29:2632-2637 (2006); Nonaka et al., Diabetes Res. Clin. Prac. 79:291-298 (2008)). HbAlc≧6.5% is a criterion for the diagnosis of diabetes, according to the American Diabetes Association. Further, there exists a controversy in the literature about whether agents that target GLP-1 action or breakdown also stimulate pancreatitis, a risk factor for the later development of pancreatic cancer (Anderson and Trujillo, Ann. Pharmacother. 44:904-909 (2010); Elashoff et al., Gastroenterology 141:150-156 (2011)).
There remains a need in the art for additional treatments for increasing insulin secretion from beta cells in individuals with T2D and in individuals at risk for developing T2D.